The [4+2] cycloaddition reaction between dienes and compounds containing a carbonyl group provides one of the most direct methods available for the synthesis of six-membered oxygen-containing heterocycles.
The hetero Diels-Alder (HDA) reaction has been studied extensively as a potential route for the preparation of oxygen-containing heterocycles, a class of biologically important molecules. Notwithstanding, the scope of the HDA reaction remains extremely limited. Nearly all such known cycloadditions have been reported using aldehydes and, even then, require highly specialized reaction conditions, such as high temperatures, high pressures, or Lewis acid catalysis.
For steric and electronic reasons, the ketone group is a substantially less reactive heterodienophile as compared to the aldehyde group. As a result, there have been extremely few reports of successful HDA reactions using simple ketones. Moreover, the use of ketones in these types of reactions is far from having general applicability. Accordingly, the development of a HDA reaction that is suitable for use with heterodienophiles such as ketones would be extremely advantageous.
Conventional methods for catalyzing asymmetric Diels-Alder reactions typically use metals and Lewis acids, which are often undesirable from the point of view of cost as well as safety (e.g., the presence of trace amounts of residual metals in the Diels-Alder cycloadduct may limit the pharmaceutical use of that compound due to strict federal regulations). Accordingly, the development of metal-free asymmetric variants of the Diels-Alder and HDA reaction would be highly desirable.